Field of the Invention
The present invention relates to compounds which inhibit phosphoinositide 3-kinases (hereinafter PI3K). More particularly, the present invention relates to compounds that are indolizine derivatives, methods of preparing such compounds, pharmaceutical compositions containing such a compound, and therapeutic uses of such a compound.
More particularly, the compounds of the present invention are inhibitors of the activity or function of the Class I of PI3K, and more specifically, they are inhibitors of the activity or function of PI3Kα, PI3Kβ, PI3Kδ and/or PI3Kγ isoforms of the Class I PI3K.
Therefore, the compounds of the present invention may be usefed in the treatment of many disorders associated with PI3K enzymes mechanisms, such as respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and cough; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis and multiple sclerosis; inflammatory disorders including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematologic malignancies; cystic fibrosis; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; organ transplantation and in particular in transplant rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain, trigeminal neuralgia, central pain and respiratory infections, airways damage, treatment and/or prevention of airway injury in patients with PI3Kδ mutations.
Discussion of the Background
In biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Specifically, PI3K enzymes are lipid enzyme kinases that can phosphorylate phosphoinositides (PIs) at the 3′-hydroxyl group of the inositol ring (Panayotou et al, Trends Cell Biol 2:358-60 (1992) which is incorporated herein by reference in its entirety). It is well known that PIs, localized in the plasma membranes, can act as second messengers in signaling cascades by docking proteins containing pleckstrin-homology (PH), FYVE, PX and other phospholipid-binding domains (Vanhaesebroeck B et al, Annu. Rev. Biochem 70, 535-602, 2001; Katso R et al, Annu. Rev. Cell Dev. Biol. 17, 615-675, 2001, which are incorporated herein by reference in their entireties).
Therefore, PIs can act as second messengers in many cellular processes including signal transduction, regulation of membrane trafficking and transport, cytoskeleton organization, cell survival and death, and many other functions.
PIs may be bound to the lipid bilayer of the cell membrane via two fatty acids that are attached to the cytosolic inositol ring via a glycerol phosphate linker. PIs inositol ring can be phosphorylated by PI3K enzymes, leading to the regulation of cellular growth, survival and proliferation. For this reason, PIs phosphorylation by PI3K enzymes is one of the most relevant signal transduction events associated with mammalian cell surface receptor activation (Cantley L C, Science 296, 1655-7, 2002; Vanhaesebroeck B et al, Annu. Rev. Biochem 70, 535-602, 2001, which are incorporated herein by reference in their entireties).
The PI3K enzymes have been divided into three classes: Class I PI3K, Class II PI3K, and Class III PI3K, on the basis of sequence homology, structure, binding partners, mode of activation, and substrate preference (Vanhaesebroeck B et al, Exp. Cell Res. 253(1), 239-54, 1999; and Leslie N R et al, Chem. Rev. 101(8), 2365-80, 2001, which are incorporated herein by reference in their entireties).
Class I PI3K convert phosphoinositide-(4,5)-diphosphate (PI(4,5)P2) to phosphoinositide-(3,4,5)-triphosphate (PI(3,4,5)P3), which functions as a second messenger. The signaling cascade activated by the increase in intracellular levels of PI(3,4,5)P3 is negatively regulated through the action of 5′-specific and 3′-specific phosphatases (Vanhaesebroeck B et al., Trends Biochem. Sci. 22(7), 267-72, 1997; Katso R et al, Annu. Rev. Cell Dev. Biol. 17, 615-75, 2001; and Toker A, Cell. Mol. Life Sci. 59(5), 761-79, 2002, which are incorporated herein by reference in their entireties).
Class II PI3K enzymes are the most recently identified class of PI3K and their exact function is still unclear.
Class III PI3K enzymes consists of a single family member which is structurally related to Class I PI3K enzymes and appears to be important in endocytosis and vesicular trafficking. However, there are some evidences showing that Class III PI3K may be relevant in immune cell processes, such as phagocytosis and Toll-like receptor (TLR) signaling.
Class I PI3K enzymes can be further divided in class IA and class IB on the basis of their activation mechanisms.
In more detail, Class IA PI3K enzymes comprises three closely related isoforms: PI3Kα, PI3Kβ and PI3Kδ, while Class IB comprises only the PI3Kγ isoform. These enzymes are heterodimers composed of a catalytic subunit known as p110, with four types: alpha (α), beta (β), delta (δ) and gamma (γ) isoforms, constitutively associated with a regulatory subunit. The first two p110 isoforms (α and β) are ubiquitously expressed and involved in cellular differentiation and proliferation. Consequently, PI3Kα and PI3Kβ enzymes have been extensively studied as targets for the development of new chemotherapeutic agents.
Otherwise, p110δ and p110γ isoforms are mainly expressed in leukocytes and are important in the activation of the immune response, such as leukocytes migration, B and T cells activation and mast cells degranulation. Therefore, PI3Kδ and PI3Kγ isoforms are very relevant in inflammatory respiratory diseases and in cancer.
Presently, the inhibitor derivatives of PI3K enzymes known in the art could generally inhibit said isoforms (alpha α, beta β, delta δ and gamma γ isoforms) and they could act on the individual roles played in various diseases by said specific isoforms.
Many genetic variants of the PI3Kδ isoform have been described in the literature (Angulo et al., Science 2013, 342, 866-871; Kracker et al. J. Clinic. Immunol. 2014, 134, 233-234; Lucas et al. Nature Immunology 2014, 15, 88-97, which are incorporated herein by reference in their entireties). Some of them involve the catalytic domain (e.g. E1021K) whereas others take place in different enzyme regions (e.g. N334K of the C2 domain). Considering that PI3K activation seems to depend on domain-domain interactions or interactions with other proteins, these mutations might lead to a change in the enzyme stability and affect enzyme activation. Furthermore, the role of PI3K mutations in immunodeficiency has been described (see references above). Patients with these mutations may develop respiratory infections, damage to the airway wall and lung parenchyma.
Therefore, specific activity assays of Class IA inhibitors for one specific PI3Kα, PI3Kβ, PI3K δ and PI3Kγ isoform over another have been extensively developed in order to discern the suitable profile for the treatment of disorders associated with PI3K enzymes mechanisms. Such disorders could, for example, include respiratory diseases selected from idiopathic chronic cough, cough-variant asthma, cough associated with thoracic tumour or lung cancer, viral or post-viral cough, upper airways cough syndrome (UACS) or post nasal drip cough, or cough associated with gastro-oesophageal reflux disease both acid and non-acid, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), interstitial lung disease, idiopathic pulmonary fibrosis (IPF), congestive heart disease, sarcoidosis, infections (such as whooping cough), viral infections including viral respiratory tract infections and viral exacerbation of respiratory diseases; non-viral respiratory infections including aspergillosis and leishmaniasis; allergic diseases including allergic rhinitis and atopic dermatitis; autoimmune diseases including systemic lupus erythematous, rheumatoid arthritis and multiple sclerosis; inflammatory disorders including inflammatory bowel disease; cardiovascular diseases including thrombosis and atherosclerosis; hematologic malignancies; neurodegenerative diseases; pancreatitis; multiorgan failure; kidney diseases; platelet aggregation; cancer; sperm motility; transplantation rejection; graft rejection; lung injuries; and pain including pain associated with rheumatoid arthritis or osteoarthritis, back pain, general inflammatory pain, post hepatic neuralgia, diabetic neuropathy, inflammatory neuropathic pain (trauma), trigeminal neuralgia and central pain.
In view of the number of pathological responses which are mediated by PI3K enzymes, there is a continuing need for inhibitors of PI3K enzymes which can be useful in the treatment of many disorders.